2023 Volume 30 Issue 7 Pages 786-794
Aims: Renal dysfunction is an independent predictor of adverse outcomes in patients with coronary artery disease (CAD). However, the prognostic impact of mid-term changes in renal dysfunction status remains unclear. This study aimed to investigate the impact of mid-term changes in renal dysfunction status on long-term clinical outcomes in CAD patients who underwent percutaneous coronary intervention (PCI).
Methods: We enrolled 382 consecutive patients with CAD who underwent PCI. Renal dysfunction was defined as a reduced estimated glomerular filtration rate (eGFR) of ＜60 mL/min/1.73m2. Renal dysfunction status was evaluated at baseline and 1-year follow-up after PCI. We divided the study population into three groups: persistent renal dysfunction, new-onset renal dysfunction, and no or improved renal dysfunction at 1-year follow-up as compared with on baseline. The endpoints of this study were composite events, including all-cause death, acute coronary syndrome, target vessel revascularization, and stroke.
Results: At baseline, renal dysfunction was observed in 77 patients (20%). At the 1-year follow-up, new-onset renal dysfunction was observed in 46 patients (12%), and 59 patients (15%) had persistent renal dysfunction. Kaplan-Meier analysis revealed a significantly higher event rate in patients with persistent renal dysfunction and new-onset renal dysfunction (log-rank test, P=0.0003). In the multivariate Cox proportional hazards analysis, persistent renal dysfunction and new-onset renal dysfunction were independently associated with composite events after adjusting for confounding factors (adjusted hazard ratios 4.08 and 2.64, 95% confidence intervals 1.72-9.57 and 1.03-6.31, P=0.0016, P=0.0045, respectively).
Conclusion: Persistent and new-onset renal dysfunction at 1-year follow-up were associated with unfavorable outcomes in patients with CAD who underwent PCI.
The worldwide prevalence of chronic kidney disease (CKD) is reported to exceed 10% in the general population, and CKD is recognized as a global public health concern1). The prevalence of CKD in patients with coronary artery disease (CAD) is increasing with the increase in the aging population2, 3). CKD is also associated with CAD severity4). Furthermore, CKD has been associated with poor outcomes in patients with CAD5). In contrast, complete revascularization has been reported to improve the prognosis of patients with CAD, despite the presence of CKD6).
Worsening renal function has been reported to be associated with unfavorable prognosis in patients with CAD7-9). Worsening renal function is also associated with in hospital mortality and coronary vascular complications in patients with acute coronary syndrome10). Furthermore, the estimated glomerular filtration rate (eGFR) at baseline and worsening renal function are associated with long-term mortality in patients with acute myocardial infarction undergoing percutaneous coronary intervention (PCI)11).
However, the prognostic impact of mid-term changes in renal function status on clinical outcomes in patients with CAD who undergo PCI has not been adequately addressed. The aim of the present study was to clarify the association of renal function status at the 1-year post-PCI follow-up with prognosis in CAD patients who underwent PCI.
This is an observational, single-center, and prospective study. We enrolled 670 consecutive CAD patients who underwent PCI at our hospital between January 2013 and December 2017. We excluded 266 patients with missing follow-up data for renal function 1-year after PCI, 19 patients with end-stage renal disease undergoing hemodialysis, and two patients with incomplete datasets. The remaining 382 patients were included in this study.
Acute coronary syndrome (ACS) was defined as ST-segment elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), or unstable angina. STEMI was diagnosed based on (1) typical chest pain lasting ＜30 min, (2) ST-segment elevation in at least two contiguous leads or left bundle-branch block on electrocardiogram (ECG), and (3) typical increase in cardiac-specific troponin T (TnT) levels exceeding the 99th percentile of a normal reference population. NSTEMI was diagnosed based on (1) typical chest pain lasting ＜30 min, and (2) typical increase in TnT levels without new ST-segment elevation on ECG. Unstable angina was diagnosed as (1) new-onset angina, accelerated angina, or angina at rest without an increase in TnT levels. New-onset angina was diagnosed as angina in which less than two months had elapsed from the date of symptoms onset. Accelerated angina was diagnosed as angina in which symptoms were more frequent and severe, longer, or precipitated by distinctly less exertion than previously, while the patient was in a stable condition. Stable CAD was diagnosed by significant coronary artery stenosis with either symptomatic or confirmed ischemia, using noninvasive testing.
Angiographical coronary stenosis was assessed according to the American College of Cardiology / American Heart Association / Society for Cardiovascular Angiography and Interventions (ACC / AHA / SCAI)12). Significant coronary stenosis was defined as a visually estimated diameter stenosis severity of ≥ 70% for non-left main disease and ≥ 50% for left main disease.
PCI was performed based on contemporary standard techniques and current guidelines13, 14). After PCI, the patients in the present study received aspirin (100-200 mg/day) and clopidogrel (75 mg/day), or prasugrel (3.75 mg/day).
Demographic and clinical data including age, sex, smoking, atrial fibrillation (AF), family history of CAD, previous myocardial infarction, chronic heart failure (CHF), clinical presentation of ACS and stable CAD, and medications at discharge were collected from patients’ medical records and through interviews. Body mass index (BMI) was calculated based on the patient’s weight and height measured during hospitalization. Diagnoses of hypertension, diabetes mellitus, and hyperlipidemia were established based on medical records or a history of related medical therapy.
Informed consent was obtained from all patients prior to participation, and the protocol was approved by the Human Investigation Committee (2020-344). All procedures were performed in accordance with the Declaration of Helsinki.
Laboratory AssessmentUrine and venous blood samples were obtained early in the morning, within 24 h after admission. Proteinuria, serum creatinine, hemoglobin (Hb), and C-reactive protein (CRP) levels were measured using routine laboratory methods.
Assessment of Renal FunctionThe eGFR was calculated using the Modification of Diet in Renal Disease equation with the Japanese coefficient15). Renal dysfunction was defined as reduced eGFR (＜60 mL/min/1.73 m2). Renal function was evaluated at baseline before PCI, and at 1-year follow-up after PCI. We divided the study population into three groups: (1) persistent renal dysfunction, patients who had renal dysfunction both at baseline and 1-year follow-up; (2) new-onset renal dysfunction, patients who did not have renal dysfunction at baseline and who developed renal dysfunction at 1-year follow-up; (3) no renal dysfunction, patients who did not have renal dysfunction both at baseline and at 1-year follow-up, or who had renal dysfunction at baseline and did not have renal dysfunction at 1-year follow-up due to improved renal function.
Endpoints and Follow-UpPatients were prospectively followed up for a median duration of 1381 days (interquartile range 1074-1537 days). Clinical follow-up data were obtained from outpatient record reviews and telephone interviews. The endpoints of the present study were composite events including all-cause death, ACS (as previously defined), target vessel revascularization, and stroke. Target vessel revascularization is defined as any repeat PCI or surgery with coronary artery bypass graft of the target lesion for ischemic symptoms and events.
Statistical AnalysisThe normality of continuous variables was assessed using the Shapiro-Wilk test. Continuous data are expressed as mean±standard deviation (SD), and skewed data are presented as medians with interquartile ranges. Unpaired Student’s t-test and Chi-squared test were performed to compare continuous and categorical variables, respectively. The Mann-Whitney U-test was performed for skewed data. Differences among the three groups around CKD status were assessed through and analysis of variance (ANOVA), with Tukey-Kramer Honest Significant Difference test for parametric variables, or Steel-Dwass test for nonparametric variables. Univariate and multivariate analyses with Cox proportional hazards regression were used to determine significant predictors of cardiovascular events. Since CRP levels were not normally distributed, we used loge CRP values in Cox proportional hazard analyses. Predictors that were significant in the univariate analysis were included in the multivariate analysis. Cumulative overall and event-free survival rates were computed using the Kaplan-Meier method and compared using the log-rank test. Statistical significance was set at P＜0.05. All statistical analyses were performed using JMP version 11 (SAS Institute, Inc.; Cary, NC, USA).
The baseline characteristics of the 382 patients who underwent PCI are shown in Table 1. The mean age was 68.7±10.2 years, and there were more men than women (n=299, 78%). The prevalence of hypertension, diabetes mellitus, hyperlipidemia, current smoking, Atrial fibrillation (AF), family history of CAD, chronic heart failure (CHF), and previous myocardial infarction was 272 (71%), 160 (42%), 204 (53%), 228 (60%), 48 (13%), 73 (19%), 38 (10%), and 54 (14%), respectively. The clinical presentations of ACS were observed as STEMI in 86 (23%) patients, NSTEMI in 41 (11%) patients, and unstable angina in 25 (7%) patients. There were 231 (60%) patients with stable CAD. The 3 vessel disease and left main disease was observed in 37 (10%) and 4 (%) patients, respectively. The mean eGFR and Hb levels were 77.5±21.2 ml/min/1.73m2, and 13.0±1.8 g/dl, respectively.
| All patients (n= 382) | No Renal Dysfunction (n= 277) | New-onset Renal Dysfunction (n= 46) | Persistent Renal Dysfunction (n= 59) | P value | |
|---|---|---|---|---|---|
| Age, years | 68.7±10.2 | 66.6±10.3 | 73.8±7.9＊ | 74.4±7.4＊ | ＜0.0001 |
| Males, n (%) | 299 (78) | 226 (82) | 29 (63) | 44 (75) | 0.0140 |
| Body mass index, kg / m2 | 24.2±3.5 | 24.4±3.6 | 24.1±3.4 | 23.7±3.1 | 0.4055 |
| Hypertension, n (%) | 272 (71) | 186 (67) | 34 (74) | 52 (88) | 0.0049 |
| Diabetes mellitus, n (%) | 160 (42) | 116 (42) | 18 (39) | 26 (44) | 0.8786 |
| Hyperlipidemia, n (%) | 204 (53) | 150 (54) | 26 (57) | 28 (48) | 0.5827 |
| Smoker, n (%) | 228 (60) | 176 (64) | 20 (43) | 32 (54) | 0.0240 |
| AF, n (%) | 48 (13) | 29 (10) | 6 (13) | 13 (22) | 0.0515 |
| Family history of CAD, n (%) | 73 (19) | 57 (21) | 10 (22) | 6 (10) | 0.1618 |
| Previous MI, n (%) | 54 (14) | 37 (13) | 8 (17) | 9 (15) | 0.7405 |
| CHF, n (%) | 38 (10) | 21 (8) | 8 (17) | 9 (15) | 0.0530 |
| Clinical presentation, n (%) | |||||
| STEMI | 86 (23) | 65 (23) | 11 (24) | 10 (17) | 0.5372 |
| NSTEMI | 41 (11) | 30 (11) | 7 (15) | 4 (7) | 0.3809 |
| Unstable angina | 25 (7) | 19 (7) | 2 (4) | 4 (7) | 0.8134 |
| Stable CAD | 231 (60) | 164 (59) | 26 (57) | 41 (69) | 0.2874 |
| Complexity of disease, n (%) | |||||
| 1VD | 249 (65) | 179 (64) | 32 (70) | 38 (64) | 0.7978 |
| 2VD | 92 (24) | 71 (26) | 8 (17) | 13 (22) | 0.4253 |
| 3VD | 37 (10) | 24 (9) | 6 (13) | 7 (12) | 0.5535 |
| LMT | 4 (1) | 3 (1) | 0 (0) | 1 (2) | 0.5562 |
| Proteinuria, n (%) | 93 (24) | 62 (22) | 10 (22) | 21 (36) | 0.1063 |
| Blood biomarkers | |||||
| eGFR, ml/min/1.73m2 | 77.5±21.2 | 85.2±18.1 | 69.3±9.6＊ | 47.9±9.8＊† | ＜0.0001 |
| Hb, g/dl | 13.0±1.8 | 13.4±1.6 | 12.4±1.7＊ | 12.0±2.0＊ | ＜0.0001 |
| CRP, mg/dl | 0.18 (0.10-1.05) | 0.16 (0.10-0.98) | 0.35 (0.10-1.92) | 0.16 (0.10-0.82) | 0.1441 |
| Medications, n (%) | |||||
| Aspirin, n (%) | 380 (99) | 275 (99) | 46 (100) | 59 (100) | 0.8264 |
| P2Y12 Inhibitor, n (%) | 376 (98) | 273 (99) | 46 (100) | 57 (97) | 0.3632 |
| Oral anticoagulant agent, n (%) | 64 (17) | 39 (14) | 10 (22) | 15 (25) | 0.0689 |
| Statin, n (%) | 338 (89) | 248 (90) | 41 (89) | 49 (83) | 0.3236 |
| ACE inhibitors and/or ARBs | 280 (74) | 196 (71) | 34 (74) | 50 (85) | 0.1028 |
| β blockers | 191 (50) | 138 (51) | 25 (54) | 28 (47) | 0.7813 |
| Loop diuretics | 36 (9) | 19 (7) | 8 (17) | 9 (15) | 0.0279 |
Data are presented as mean±S.D or % unless otherwise indicated; IQR, interquartile range; CKD, chronic kidney disease; AF, atrial fibrillation; CAD, coronary artery disease; CHF, chronic heart failure; MI, myocardial infarction; STEMI, ST-segment elevation myocardial infarction; NSTEMI, non-STEMI; VD, vessel disease; LMT, left main trunk; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; CRP, C reactive protein; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.
＊P＜0.05 vs. No CKD group, †P＜0.05 vs. New-onset
Patients with persistent and new-onset renal dysfunction were significantly older and had a higher prevalence of hypertension than those without renal dysfunction. Patients with persistent and new-onset renal dysfunction had a significantly higher treatment rate with loop diuretics than those without renal dysfunction. Patients with new-onset renal dysfunction were more likely to be female and had a lower prevalence of current smoking than those in the other groups. eGFR and Hb levels were significantly lower in patients with persistent renal dysfunction and new-onset renal dysfunction than in those without renal dysfunction. There were no significant differences in BMI, CRP, prevalence of diabetes mellitus, hyperlipidemia, AF, family history of CAD, previous MI, CHF, clinical presentation, complexity of disease, or treatment rate with aspirin, P2Y12 inhibitor, oral anticoagulant agent, statin, ACE inhibitor or ARB, and β-blocker (Table 1).
Change in Renal Function Status After PCIAt baseline, renal dysfunction was observed in 20% (n=77) of the patients, and 80% (n=305) of the patients had normal renal function. A 12% (n=46) of patients developed renal dysfunction within a year after PCI, whereas 15% (n=59) of patients had persistent renal dysfunction status. The remaining 73% (n=277) of patients had maintained normal renal function within a year after PCI (Fig.1). The eGFR at 1-year after PCI in patients with no renal dysfunction, new-onset renal dysfunction, and persistent renal dysfunction was 81.6±14.1, 53.2±8.1, and 46.7±9.6 ml/min/1.73m2, respectively (data were not shown).
Renal dysfunction was observed in 20% (n=77) of patients at baseline. 12% (n=46) of patients developed renal dysfunction during the 1-year follow-up period. 15% (n=59) of patients had persistent renal dysfunction status during the 1-year follow-up period. PCI, percutaneous coronary intervention.
There were 38 composite clinical events during the follow-up period: all-cause death, n=17; ACS, n=6; target vessel revascularization, n=8; stroke, n=7.
The Kaplan-Meier analysis demonstrated that persistent and new-onset renal dysfunction were associated with the greatest risk among patients who underwent PCI (log-rank test, P=0.0003, Fig.2).
Kaplan-Meier analysis demonstrated a significantly higher composite event rate in patients with persistent and new-onset renal dysfunction (log-rank test, P=0.0003). PCI, percutaneous coronary intervention.
In the univariate Cox proportional hazard analysis, persistent and new-onset renal dysfunction were significantly associated with the highest risk for composite events (hazard ratios, 3.82 and 2.80; 95% confidence intervals, 1.82-7.83 and 1.14-6.30; P=0.0006 and P=0.0259, respectively). Multivariate Cox proportional hazard analysis showed that persistent and new-onset renal dysfunction were associated with the highest risk for composite events after adjusting for age, BMI, Hb, and treatment with ACE inhibitor or ARB (hazard ratios, 4.08 and 2.64; 95% confidence intervals, 1.72-9.57 and 1.03-6.31; P=0.0016 and P=0.0045) (Fig.3).
Persistent and new-onset renal dysfunction were significantly associated with the highest risk for composite events. PCI, percutaneous coronary intervention.
The subgroup prognostic analyses between new-onset and no renal dysfunction group were shown in Supplemental Fig.1 and 2.
Kaplan-Meier analysis demonstrated a significantly higher composite event rate in patients with new-onset renal dysfunction (log-rank test, P=0.0053). PCI, percutaneous coronary intervention.
New-onset renal dysfunction was significantly associated with higher risk for composite events in univariate cox proportional hazard analysis. Multivariate cox proportional hazard analysis demonstrated that new-onset renal dysfunction was not independently associated with composite events after adjustment for confounding risk factors. PCI, percutaneous coronary intervention.
In the present study, (1) renal dysfunction was observed in 20% of patients with CAD who underwent PCI at baseline; (2) at 1-year post-PCI follow-up, new-onset renal dysfunction was observed in 12% of patients; (3) Kaplan-Meier analysis demonstrated a significantly higher event rate in patients with both persistent and new-onset renal dysfunction than in those without renal dysfunction; and (4) multivariate Cox hazard analysis revealed that both persistent and new-onset renal dysfunction were significantly associated with poor clinical outcomes in CAD patients who underwent PCI.
Recently, the association between worsening renal function and poor prognosis in patient with CAD who underwent PCI was reported in various studies. A recent study demonstrated that the incidence of worsening renal function in patients with ischemic heart disease within 1-year after PCI (defined as an increase in creatinine ≥ 0.3 mg/dL) was 9.3%, and worsening renal failure was significantly associated with mortality7). Another study revealed that worsening renal function in patients with ischemic heart disease three months after PCI was related to adverse cardiac events8). Worsening renal function was also associated with mortality in patients with acute myocardial infarction11). However, there are few reports about prognostic impact of mid-term longitudinal change in renal function status. The clinical significance of persistent and new-onset renal dysfunction at 1-year after PCI in patients with CAD is remains unclear. In the present study, persistent renal dysfunction was associated with an approximately 4-fold increase in the risk of composite clinical outcomes compared to normal renal function. New-onset renal dysfunction was developed in 12% of the patients at the 1-year follow-up after PCI. Similar to persistent renal dysfunction, new-onset renal dysfunction was also associated with poor clinical outcomes compared to no renal dysfunction in the present study. Various studies have demonstrated that patients who undergo PCI with normal renal function at baseline have a lower risk of cardiovascular events than those with CKD. Our study showed the importance of follow-up for mid-term changes in renal function status, since it might grant risk stratification in CAD patients who underwent PCI.
The mechanism of new-onset renal dysfunction in the present study was unclear. Various factors influence post-PCI renal function deterioration in CAD patients. Previous studies have revealed an association between renal dysfunction progression and aging, hypertension, diabetes, and dyslipidemia2, 3, 16). The ISCHEMIA-CKD trial showed that contrast-associated acute kidney injury occurred in 7.9% of the invasive-strategy group, which might be related to atheroembolic complications of coronary angiography and revascularization17). The previous studies revealed the association between diuretic use and decline in eGFR18, 19). Furthermore, the association between heart failure and renal dysfunction has been demonstrated as cardio renal syndrome20). In the present study, patients with renal dysfunction were significantly older and had a higher prevalence of hypertension and treatment with loop diuretics than those without renal dysfunction. In addition, patients with renal dysfunction had a tendency of higher prevalence rate of CHF. These results might explain the renal dysfunction progression at the 1-year post-PCI follow-up.
In the present study, we demonstrated that new-onset and persistent renal dysfunction was associated with poor clinical outcomes in CAD patients who underwent PCI. Therefore, prevention of renal dysfunction progression might lead to favorable prognosis. We revealed that the prevalence rates of hypertension, CHF, and use of loop diuretics were higher in patients with renal dysfunction compared to those without. The optimal medical treatment for hypertension and CHF, and optimal fluid management might be associated with prevention of renal dysfunction progression. In addition, the prevention of contrast-induced nephropathy is needed to protect renal function in CAD patients who underwent PCI. Previous studies have reported that procedural isotonic fluid hydration or injections of sodium bicarbonate decrease the incidence of contrast-induced nephropathy21, 22). More recently, sodium glucose cotransporter 2 (SGLT2) inhibitors have been reported to show protective effect for renal function in patients with CKD and diabetes mellitus23). These treatments might have possibility to protect renal function in CAD patients who underwent PCI.
This study has several limitations. First, this was a single-center study with a relatively small sample size. As the number of events was also small and the formal sample size was missing, the statistical power for predicting clinical hard endpoints was weak. Second, approximately 40% of total cohort population were excluded in the present study. This exclusion might cause selection bias and influence our results. Third, there is a possibility that the prognostic impact of changes in renal function status differs between acute coronary syndrome and stable CAD. Previous studies have demonstrated that acute kidney injury is frequently observed in patients with ACS, which is driven by hemodynamic instability such as cardiogenic shock and acute heat failure24, 25). Forth, there were some patients who recovered from renal dysfunction at 1-year follow-up after PCI, and the reason for renal function improvement remains unclear. The previous study demonstrated that renal function gradually improved after treatment of cardiogenic shock26). The hemodynamic changes in acute phase might affect renal function. Fifth, we did not have detailed information on the PCI procedure for each patient. For example, contrast-associated acute kidney injury occurs after coronary revascularization17). In the present study, PCI related kidney injury might have affected the change in the renal function status. Thus, information regarding the PCI procedure is important. Further studies are required to clarify the extent of these limitations.
Both persistent and new-onset renal dysfunction at 1-year follow-up were associated with unfavorable outcomes in patients with CAD who underwent PCI. The change in renal function status at the 1-year follow-up provides useful information for the risk stratification of CAD patients who underwent PCI.
The authors declare no conflicts of interest.
The authors thank Editage (www.editage.jp) for English language review.
